Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extrasynaptic sites that link multiple intracellular catabolic processes responsible for irreversible neuronal death. Here, we report that cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) into the NMDA receptor NR2B protein complex in the cortex of adult mice. DAPK1 directly binds with the NMDA receptor NR2B C-terminal tail consisting of amino acid 1292-1304 (NR2B(CT)). A constitutively active DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn enhances the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 or administration of NR2B(CT) that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca(2+) influx through NMDA receptor channels at extrasynaptic sites and protects neurons against cerebral ischemic insults. Thus, DAPK1 physically and functionally interacts with the NMDA receptor NR2B subunit at extrasynaptic sites and this interaction acts as a central mediator for stroke damage.
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PMID:DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. 2014 29

Emerging evidence has suggested a significant role of long non-coding RNAs (lncRNAs) in ischemic stroke by acting as competing endogenous RNAs (ceRNAs) for microRNAs (miRNAs) to regulate certain RNA transcripts. AK038897 is an lncRNA that was reported to be upregulated in rat brains in response to transient focal ischemia. We aimed to investigate the possible regulatory role of AK038897 in ischemic stroke. We detected increased AK038897 and decreased miR-26a-5p levels in mouse brains following middle cerebral artery occlusion/reperfusion (MCAO/R) and in neuro-2A (N2a) neuroblastoma cells following oxygen-glucose deprivation and reoxygenation (OGD/R). With bioinformatics, we identified shared putative miR-26a-5p binding sites in AK038897 as well as in the 3'-UTR of death-associated protein kinase 1 (DAPK1), which is a central mediator of ischemic neuronal death. MiR-26a-5p overexpression attenuated OGD/R-induced N2a cell apoptosis. The luciferase reporter assay results confirmed that miR-26a-5p directly targets DAPK1. Further studies showed that AK038897 directly binds to miR-26a-5p and functions as a ceRNA for miR-26a-5p to regulate DAPK1. As a result, AK038897 overexpression antagonized while AK038897 knockdown enhanced the inhibitory effects of miR-26a-5p on DAPK1 expression and OGD/R-induced N2a cell apoptosis. Further, AK038897 knockdown protected against MCAO/R-induced brain injury and neurological deficits in vivo. In summary, we identified a AK038897/miR-26a-5p/DAPK1 signaling cascade as a key mechanism controlling cerebral ischemia/reperfusion injury. Pharmaceutical intervention of this cascade may provide novel therapy for ischemic insults.
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PMID:Long non-coding RNA AK038897 aggravates cerebral ischemia/reperfusion injury via acting as a ceRNA for miR-26a-5p to target DAPK1. 3070 62

DAPK (death-associated protein kinase) is a calcium/calmodulin (Ca2+/CaM) regulated serine/threonine kinase. Structurally, it assumes a multi-domain structure and participates in various apoptotic systems which imply that it may interact with a wide range of intracellular components to exert its action. DAPK plays vital roles in pro-apoptotic, apoptotic and autophagic pathways. In addition, it plays important roles in many diseases such as cancer, Alzheimer's disease, cerebral ischemia and epilepsy. Although a novel protein, DAPK's various cellular signal transduction pathways proves that it can be a target for a potential future therapeutic effects. Specific role of DAPK in the development and maintenance of the nervous system needs to be further investigated as it is involved in neurodegeneration, traumatic brain injury and neuronal development or recovery from injury. This review summarizes DAPK signaling pathways in autophagy, apoptosis, and stresses the important role it might play in the nervous system.
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PMID:Role of DAPK1 in neuronal cell death, survival and diseases in the nervous system. 3076 7

Cerebral ischemia/reperfusion (I/R) injury is an obstacle in treating ischemic stroke effectively. miR-98-5p has been reported to have the ability of reducing myocardial I/R injury. To explore the function of miR-98-5p in cerebral I/R, we established mice model of middle cerebral artery occlusion and reperfusion (MCAO/R). The level of miR-98-5p was found to be downregulated in serum of stroke patients and brain tissues of MCAO/R mice. Examination of brain tissues indicated that upregulating miR-98-5p level alleviated the infarction in MCAO/R mice. Moreover, the upregulation of miR-98-5p reduced reactive oxygen species (ROS) production and enhanced superoxide dismutase (SOD) activity in brain tissues of MCAO/R mice. These results indicating that miR-98-5p could protect against oxidative stress. Further study showed that miR-98-5p inhibited apoptosis by reducing the levels of death-associated protein kinase 1 (DAPK1), B cell lymphoma/leukmia-2 (Bcl-2) associated x protein (Bax) and cleaved caspase-3, as well as increasing the level of Bcl-2. In addition, miR-98-5p was found to protect against oxidative stress through downregulating the level of BTB domain and CNC homology 1 (BACH1) and upregulating the levels of NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1). Therefore, miR-98-5p might be a potential target to treat cerebral I/R injury.
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PMID:miR-98-5p Protects Against Cerebral ischemia/reperfusion Injury Through Anti-apoptosis and Anti-oxidative stress in Mice. 3285 43